Process of producing solutions of chloramphenicol in aqueous liquids, and composition



United States Patent PROCESS OF PRODUCING SOLUTIONS OF CHLOR-AMPHENICOIL IN AQUEOUS LIQUIDS, AND COMPOSITION Johann Daniel Achelis,Heidelberg, Rndi Gall, Mannheim-Kae'fertai, Erich Haack, Heidelberg, andWolfgang Voemel, -Mannheim, Germany, assignors to C. F. Boehringer &Soehne G.rn.b.H., Mannheim-Waidhof, Germany, a corporation of Germany NoDrawing. Filed Dec. 2, 1958, Ser. No. 777,602

Claims priority, application Germany Dec. 7, 1957 5 Claims. (Cl. 167-65)The present invention relates to solutions of chloramphenicol in aqueousliquids, and to a process of preparing such solutions.

The antibiotic chloramphenicol is readily absorbed by the body on oraladministration. For this reason it is usually given per os, forinstance, in the form of gelatine capsules or dragees. In someinstances, however, oral administration cannot be used or is ineffectivebecause the patient is not able to swallow the drug, respectively, toabsorb it. It is also frequently necessary for medical reasons to avoidthe passage of the drug through the digestive tract, for instance,during or before an operation. In some cases it is desirable to achievea rapid increase of the antibiotic level in the blood. Thus, there is aconsiderable demand for injectable solution of this valuable antibiotic.However, the preparation of such solutions meets with greatdifficulties.

Chloramphen-icol is soluble in water at room temperature only up to0.4%. This concentration is by far insufiicient for administration byintramuscular or intravenous injection. It has been found thatnon-aqeous solvents for chloramphenicol, which have been used for thepreparation of more concentrated solutions, cause severe damage to thetissue in the form of painful swellings and frequently of seriousnecroses, even if the solvent as such is physiologically inert. Thisdisadvantage is especially encountered on intramuscular injection. Thesame applies to aqueous mixtures with said solvents because the solventcontent required to provide stable solutions by far exceeds the limit ofcompatibility.

It is, therefore, understandable that injection solutions ofchloramphenicol, as they have been prepared heretofore, for instancesolutions in solvents containing a high percentage of glycols andsubstituted fatty acid amides (see, for instance, German Patent No.852,123) have not found applicationin therapy. As pharmacological testshave shown, such solutions cannot be used for intramuscularadministration on account of their damaging effect on the tissue. Thesame applies to the known crystal suspensions of chloramphenicol inwater or oil. These suspensions are highly unsatisfactory for their lowblood levels. Unsatisfactory blood levels are also obtained byadministering water soluble chloramphenicol esters which were proposedfor injection purposes. Such esters, for instance, the preferablyinvestigated 3-succinate, are water-soluble in the form of their neutralsalts, such as their sodium salts. Their solutions may be injectedalmost without causing harmful reactions. However, the biologicalefiiciency test shows that, for instance, the succinate produces a muchlower blood level than the same amount of chloramphenicol. This isprobably due to the poor hydrolysis of the succinate within the body toproduce the effective chloramphenicol.

It is one object of the present invention to provide solutions forparenteral administration which contain a high percentage ofchloramphenicol, which may be diluted with water without precipitationof the chloramphenicol, and which have no damaging effect upon thetissue when injected in therapeutically useful amounts.

Another object of the present invention is to provide a simple andeffective process of producing such highly concentrated chloramphenicolsolutions.

A further object of the present invention is to provide phenicol isincreased considerably by the addition of lower chloramphenicol esters.Solutions of chloramphenicol containing such esters can be diluted withwater without precipitation of chloramphenicol. The application of thisprinciple permits parenteral administration of chloramphenicol,preferably intramuscular administration thereof, which, in .many' cases,is highly desirable, in an amount sufficient to produce the desiredantibiotic eifects without causing damage to the body, such as necroticchanges of the tissue.

The term lower esters indica-ta esters having a maximum of 10 carbonatoms Within the ester group and will be used hereinafter and in theclaims annexed hereto. With higher esters a significant decrease inantibiotic efiiciency is observed. Suitable esters are not only themono-esters of chloramphenicol but also the di-esters and mixturesthereof. The esters may be esters of monoor polyvalent organic acids andtheir substitution products as well as of inorganic acids, such asnitric acid, hydrochloric acid, phosphoric acid, and the like.Especially effective esters are the following esters of organic acids:

Esters of lower aliphatic monoor'polycarboxylic acids such as thefollowing esters:

O -acetate, O ,O -diaceta'te, O -maleate, 0 -succin'ate. Esters ofesterified and etherified hydroxy lower fatty acids such as thefollowing esters:

-O -ethox-y acetate, O -ethoxy acetate, O ,O -di-(ethoxy acetate), O-methoxy ethoxy acetate, o O -di-(methoxy ethoxy acetate), O -rnethoxyethoxy ethoxy acetate, O ,O -di-(methoxy ethoxy ethoxy acetate),

O -tetrahydrofurfuryloxy acetate, O ,O di-(tetrahydrofurfuryloxyacetate), O -1,3-dimethoxy isopropoxy acetate, O -methoxy acetate, O ,O'-di-(methoxy acetate), O acetoxy acetate, O -diacetyl tartrate. 1Esters of partly esterified aliphatic polycarboxylic acids,

such as the followingesters:

O -mono-methyl succinate, O -mono-methyl malonate.- Esters of loweraliphatic keto carboxylic acids, such as the following ester: O -acetoacetate. Esters of 'monocyclic aromatic 'dicarboxylic esters, such asthe following ester: o -p'hthalate.

The solubility increasing and stabilizing effect of such esters lisapparently not principally connected with their, own solubility inwateror, respectively, with the solubility of their salts in water; mostof them are, in fact, only difliculty soluble therein. However, incarrying out the solvents'must be inert to chloramphenicol and itsesters.

They must :also be physiologically inert, at least in the 3,044,936 IPatented July 17, 196 2 j 3 concentrations in which they are usedtherapeutically. Solvents which meet with these conditions are, amongothers, the following:

Polyethylene glycol ethers, such as diethylene glycol dimethyl ether;

Dimethyl sulfoxide;

N,N-di-(lower alkyl) lower alkanoic acid amides such as dimethylformamide, dimethyl acetamide, diethyl formamide, diethyl acetamide;

Glycerol methyl ether;

Tetrahydrofurfuryl methyl ether; and others.

To carry out the present invention it is not necessary to use thesolubilizing or, respectively, stabilizing ester as such. The ester mayalso be formed-and this is the preferred method in some cases-whenpreparing the chloramphenicol solution, whereby, of course, an excess ofchloramphenicol is used. For this purpose the corresponding acidanhydride is added to the mixture of solvent and chloramphenicol. Ifesters of acids are used which contain a salt-forming group, it is thepreferred procedure to form the salt by adding an equivalent amount ofan alkali hydroxide or another basic substance, for instance, of aphysiologically inert amine. In certain special instances it might beadvisable to use additionally a known solubilizing agent to causefurther stabilization of the resulting solution, such as urea or itssubstitution products, or urethanes. This elfect is very surprisingbecause such known solubilizing aids alone do not produce anysubstantial increase in solubility of chloramphenicol in aqueousliquids.

The process of increasing the solubility of chloramphenicol in aqueousliquids by means of lower chloramphenicol esters according to thepresent invention is, as stated above, of considerable importance forthe preparation of injectable solutions of this valuable antibiotic. Theresulting injectable solutions which may contain 30% and more of theeffective drug, are well tolerated especially by the tissue becausetheir content of organic solvents, if they are used for preparing theinitial ester solution, is always within the limit of compatibility,whereas the esters of chloramphenicol are physiologically inert andcontribute to the desired therapeutieal effect due to their more or lessrapid hydrolysis to chloramphenicol.

The injectable liquids according to the present invention are quitestable. However, due to the sensitivity of most esters againsthydrolysis, it is advisable to first prepare a solution containing thechloramphenicol and the ester and, if necessary, the solubilizing aid inan anhydrous organic solvent of the above mentioned type. This solution,which can be stored for an unlimited period of time, represents thestock solution. It is diluted with water shortly before its use. Thephysician may prepare the final dilution. Further handling of theinjectable solutions according to the present invention, for instance,adjustment of its pH-value, sterilization, and the like is effected withthe usual care.

The following examples serve to illustrate the present inventionwithout, however, limiting the same thereto.

Example 1 A suspension containing 4 g. of chloramphenicol in a solutionof 5.5 g. of chloramphenicol-Ownccinate in the form of its sodium saltin 100 cc. of water is caused to dissolve by heating for a short periodof time. The resulting solution remains clear after cooling whereas asolution of 0.6 g. of chloramphenicol in 100 cc. of warm water showsimmediate precipitation of crystals when cooled.

Example 2 When a solution containing 1.0 g. of chloramphenicol in 2.0cc. of dimethyl sulfoxide is diluted with cc. of water, chloramphenicolprecipitates immediately. However, if 1.4 g. of the sodium salt ofchloramphenicol-O succinate are added to the starting solution, a clearsolution results on the addition of the same amount of water. Thissolution does not precipitate even after several days.

Example 3 A solution containing 1.89 g. of chloramphenicol, 2.0 g. ofdimethyl urea, and 0.15 g. of chloramphencol-O methoxy ethoxy acetate in2 cc. of dimethyl sulfoxide remains clear after dilution with waterwhereas, without the addition of the chloramphenicol ester, thechloramphenicol is precipitated by the addition of water.

Example 4 500 mg. of chloramphenicol and 635 mg. of chloram- PhBIIlCOl-O-SUCClHQlfi are dissolved in a mixture of 0.4 cc. of dimethyl sulfoxideand 0.2 cc. of diethylene glycol dimethyl ether. Upon addition of 160mg. of sodium carbonate and distilled water in an amount sufiicient toyield a volume of 4 cc., a clear solution containing 25% ofchloramphenicol is obtained.

Example 5 10 g. of chloramphenicol and 13.8 g. of the sodium salt ofchloramphenicol-O -succinate are dissolved in 16 cc. oftetrahydrofurfuryl methyl ether. In order to obtain a 25%chloramphenicol solution, water is added to a volume of cc.

Example 6 A solution containing 2.0 g. of chloramphenicol and 0.206 g.of succinic acid anhydride in 1.4 cc. of N,N- dimethyl methoxy acetamideis heated at 110 C. for 60 minutes. Upon adding 5.1 cc. of a 4.3% sodiumcarbonate solution, a clear solution is obtained with a totalchloramphenicol content of 25 Example 7 A solution of 2.0 g. ofchloramphenicol in 1.6 cc. of diethylene glycol dimethyl ether soldunder the trademark Diglyme is mixed with 0.3 g. of succinic acidanhydride. The resulting mixture is heated to 110 C. for minutes. Byadding a solution of 350 mg. of sodium carbonate in 4.9 cc. of waterthereto, a clear solution is obtained.

Example 8 A solution of 2.0 g. of chloramphenicol in 0.9 cc. ofdiethylene glycol dimethyl ether and 0.5 cc. of dimethyl acetamide ismixed with 0.25 g. of maleic acid anhydride. The mixture is heated to C.for 60 minutes. By adding a solution of 300 mg. of sodium carbonate in5.1 cc. of water, a clear solution is obtained.

Example 9 0.5 g. of chloramphenicol and 0.69 g. ofchloramphenicol-3-N,N-dimethy1 glycinate hydrochloride correspond ing to0.5 g. of chloramphenicol, are dissolved in 1.0 cc. of dimethyl methoxyacetamide. The resulting solution is diluted with water to a volume of 4cc. A clear solution with a total chloramphenicol content of 25% isobtained.

The same results are obtained When chloramphenicol- 3-glycinate sulfateor chloramphenicol-3-betainate hydrochloride are used in place ofchloramphenicol-LEN- dimethyl glycinate hydrochloride.

Of course, other lower esters of chloramphenicol may be employed forsolubilizing chloramphenicol and stabilizing its aqueous solutions asthey have been mentioned hereinabove, may be used by those skilled inthe art in accordance with the principles set forth herein and in theclaims annexed hereto.

If esters of acids are used which contain a salt-forming group, it ispreferred to form the salts by addition of a basic substance. In thatcase, not only alkali hydroxides or carbonates can be used but alsoammonia or organic amines, e.g. butyl amine, methoxy propyl amine etc;

We claim:

1. The stable solution of chloramphenicol in an aqueous liquidcontaining dissolved therein choramphenicol and, as solubilizing agent,the sodium salt of chlorarnphenico1-3-succinate, the molar ratio ofchlorarnphenicol to sodium salt being between about 1:1 and about 2: l.

2. The solution of chloramphenicol in dimethyl sulfoxide containingdissolved therein the sodium salt of chloramphenicol-3-succinate, themolar ratio of chloramphenicol to sodium salt being between about 1:1and about 2: 1, said solution being miscible with water to yield ahighly concentrated, stable, aqueous chloramphenicol solution.

3. The solution of chloramphenicol in tetrahydrofurfuryl methyl ethercontaining dissolved therein the sodium salt ofchloramphenicol-3-succinate, the molar ratio of chloramphenicol tosodium salt being between about 1:1 and about 2:1, said solution beingmiscible with water to yield a highly concentrated, stable, aqueouschloramphenicol solution.

. 4. The stable solution of chloramphenicol in an aqueone liquidcontaining dissolved therein chloramphenicol and, as solubilizing agent,a salt of chloramphenicol-3- succinate selected from the groupconsisting of its alkali metal salts and its ammonium salt, the molarratio of 1 chloramphenicol to salt being between about 1:1 andReferences Cited in the file of this patent UNITED STATES PATENTS2,586,661 Jacob Feb. 19, 1952 2,838,552 Gansau June 10, 1958 2,852,430Goebel Sept. 16, 1958 FOREIGN PATENTS 852,123 Germany Oct. 13, 1952

1. THE STABLE SOLUTION OF CHLORAMPHENICOL IN AN AQUEOUS LIQUIDCONTAINING DISSOLVED THEREIN CHORAMPHENICOL AND, AND SOLUBILIZING AGENT,THE SODIUM SALT OF CHLORAMPHENICOL-3-SUCCINATE, THE MOLAR RATIO OFCHLORAMPHENICOL TO SODIUM SALT BEING BETWEEN ABOUT 1:1 AND A BOUT 2:1.